Although the prevalence and clinical importance of Post-traumatic Stress Disorder is becoming more widely recognized, our understanding and practical management of this disorder is still very limited and there is a pressing need for broader and more innovative research approaches in this field. The clinical presentation of the illness is often complicated by comorbidity with concurrent diagnoses of depression, anxiety disorders, or substance abuse. The disorder has proven to be extraordinarily refractive to treatment by conventional approaches. There is a need, therefore, for a fuller understanding of the nature and pathogenesis of PTSD and perhaps especially more extensive investigation of the possibility that biological mechanisms may have an important role in the development and course of the disorder. Because of the well-known relationship between stress and hormonal systems, we initiated a survey which led to the finding that there were substantial and characteristic alterations in several major hormonal systems in PTSD, indicating the need for a multidimensional hormonal assessment of this disorder. As our work has progressed, we recently discovered a striking and unusual, if not unique pattern of alteration in thyroid function in PTSD, characterized by marked elevations of free and total T3, a moderate increase in total T4, but little or no change in free T4 or TSH. This pattern is associated with an increase in the T3/T4 ratio, suggesting that there is an increase in the peripheral conversion of T4 to T3, which is the main source of T3 in the body. Some studies have shown that catecholamines can increase the T4 to T3 conversion rate, and it is possible that the chronic elevation of catecholamines which we have demonstrated in PTSD might be the basis for these thyroid alterations. We have developed a number of research strategies for gaining a fuller understanding of the pathophysiology of these thyroid alterations in PTSD, including additional assessment of central HPT function with TRH infusion challenge tests, the study of other disorders with elevated catecholamines to see if T3/T4 ratios are high, the study of treatment effects with medications such as lithium, clonidine, and Prozak with a view to comparing symptom improvement and thyroid profile levels over the course of treatment, and the study of correlations between specific symptoms related in the clinical literature to thyroid hyperactivity to hormone levels in PTSD.